Does helminth treatment reduce the risk of active tuberculosis in a cohort of children from high tuberculosis risk population who have been vaccinated with BCG at birth?

Includes bibliographical references.[Background] Research in adults and older children has shown an association between Mycobacterium tuberculosis and helminth infection, with those infected with helminths at greater risk of tuberculosis. This association is believed to be on the basis that chronic helminth infection can result in a functional impairment of the immune response that is necessary to clear or control infection by Mycobacterium tuberculosis (Elias et al. 2001; Rook et al. 2006; Fincham 2001). It is thus possible that the introduction of regular deworming programmes in a vulnerable population of children under the age of five years could assist their immune systems to ward off tuberculosis infection and reduce the risk of tuberculosis disease in such a population. A randomised controlled trial to compare two methods of administering bacille Camlette-Guerin (BCG) vaccination to newborns from a high tuberculosis risk population provided an opportunity to test this hypothesis in a sub-study. [Objective] The objective of this study is to determine if young children in a high-risk tuberculosis population who have been vaccinated with BCG at birth and have been treated for helminth infection are at lower risk of tuberculosis disease than children who have been vaccinated with BCG at birth but not treated for helminth infection. [Method] A case control study nested within a cohort recruited for a separate randomised control trial to compare two methods of administering BCG vaccination was carried out. Children who presented to their local clinic or hospital with symptoms of tuberculosis or a history of exposure to tuberculosis were admitted to a case verification (CV) ward for investigation of tuberculosis. Investigation of tuberculosis included a detailed history, including past helminth treatment, physical examination, tuberculin skin test, chest radiograph, gastric washing and induced sputum for culture of tuberculosis and clinical examination. A diagnostic algorithm was developed by specialist physicians and biostatisticians to classify the children into one of five tuberculosis categories. A total of 510 children (median age 18.13 months) were included in the primary analysis of this case control study. Those defined as cases were the 328 classified as "definite or probable TB" and 182, classified as "not TB", comprised the control group. Those classified as "possible TB" or "unlikely TB" were excluded. A secondary analysis was performed that included the 337 children who had been classified as "unlikely TB" with the controls resulting in a total of 847 children (median age 18.37 months). The 328 children classified as "definite or probable TB" were defined as cases and the 519 classified as "unlikely or not TB" comprised the control group. Univariate analysis was used to explore a possible relationship between tuberculosis and helminth treatment using all the variables in the sub-study (n=510 primary analysis; n=847 secondary analysis). For both the primary and secondary analysis a multivariate logistic regression model was built using a reduced sample that had a complete set of data for all the variables: primary analysis (n=435); secondary analysis (n=724). This final model was then fitted on a more complete sample as the final variables selected had fewer missing data for the observations: primary analysis (n=493); secondary analysis (n=822). [Result] A total of 35.69% of the study sample in the primary analysis had been treated for helminth infection. The proportion of children who had been treated for helminth infection was similar in the cases and controls (35.98% and 35.16% respectively). Univariate logistic regression showed no association between tuberculosis and treatment for helminth infection: [odds ratio (OR) 1.04; 95% confidence interval (CI) 0.71 - 1.51]. Multivariate analysis adjusted for the effect of nutritional status, recorded as height for age z score (haz), number of occupants sharing the same dwelling as the child, gender and birth site showed a similar result: (OR 1.03; 95% CI 0.69 " 1.53). The OR is very close to 1 with a 95% CI that includes 1, which indicates that there is not a statistically significant association between tuberculosis and helminth treatment. In the secondary analysis, a total of 38.61% of the study sample had been treated for helminth infection. In this analysis the proportion of children who had been treated for helminth infection showed a difference between the cases and controls (35.98% and 40.27% respectively). Univariate logistic regression showed a 17% relative reduction in tuberculosis odds but this was not a statistically significant result: (OR 0.83; 95% CI 0.63 " 1.11). Multivariate analysis adjusted for the effect of haz, number of children sharing the same dwelling as the child and gender, showed a similar result: (OR 0.85; 95% CI 0.63 " 1.15). [Conclusion] The primary analysis of this observational study does not support the hypothesis that helminth treatment reduces the risk of tuberculosis disease in young children in a high-risk tuberculosis population. Although the secondary analysis showed a 15% relative reduction in tuberculosis odds after adjusting for the effect of haz, number of occupants sharing the same dwelling as the child and gender, this was not a statistically significant result. [Final Conclusion] This study does not support the hypothesis that helminth treatment reduces the risk of tuberculosis disease in young children in a high-risk tuberculosis population

Rapid diagnosis of pulmonary tuberculosis in African children in a primary care setting by use of Xpert MTB/RIF on respiratory specimens: a prospective study

Background In children admitted to hospital, rapid, accurate diagnosis of pulmonary tuberculosis with the Xpert MTB/RIF assay is possible, but no paediatric studies have been done in the primary care setting, where most children are given care, and where microbiological diagnosis is rarely available. We assessed the diagnostic accuracy of Xpert MTB/RIF in children in primary care. Methods For this prospective study, we obtained repeat induced sputum and nasopharyngeal aspirate specimens from children (<15 years) with suspected pulmonary tuberculosis at a clinic in Khayeliwtsha, Cape Town, South Africa. We compared the diagnostic accuracy of Xpert MTB/RIF with a reference standard of culture and smear microscopy on induced sputum specimens. For the main analysis, specifi city of Xpert MTB/RIF versus liquid culture, we included only children with two interpretable Xpert MTB/RIF and induced sputum culture results. Findings Between Aug 1, 2010, and July 30, 2012, we enrolled 384 children (median age 38·3 months, IQR 21·2–56·5) who had one paired induced sputum and nasopharyngeal specimen, 309 (81%) of whom had two paired specimens. Five children (1%) tested positive for tuberculosis by smear microscopy, 26 (7%) tested positive by Xpert MTB/RIF, and 30 (8%) tested positive by culture. Xpert MTB/RIF on two induced sputum specimens detected 16 of 28 culture-confi rmed cases (sensitivity of 57·1%, 95% CI 39·1–73·5) and on two nasopharyngeal aspirates detected 11 of 28 culture-confi rmed cases (sensitivity of 39·3, 23·6–57·6; p=0·18). The specifi city of Xpert MTB/RIF on induced sputum was 98·9% (95% CI 96·9–99·6) and on nasopharyngeal aspirates was 99·3% (97·4–99·8). Interpretation Our fi ndings suggest that Xpert MTB/RIF on respiratory secretions is a useful test for rapid diagnosis of paediatric pulmonary tuberculosis in primary care. Funding National Institutes of Health, National Health Laboratory Services Research Trust, the Medical Research Council of South Africa, the National Research Foundation South Africa, the European and Developing Countries Clinical Trials Partnership

Analysis of queries from nurses to the South African National HIV & TB Health Care Worker Hotline

Background. Since 2008, the Medicines Information Centre (MIC) has run the South African National HIV & TB Health Care Worker Hotline which provides free information on patient treatment to all healthcare workers in South Africa. With the introduction of nurse-initiated management of antiretroviral therapy (NIMART) in the public sector, the need for easy access to HIV and tuberculosis (TB) information has increased, especially among nurses. The hotline aims to provide this, most importantly to nurses in rural areas, where clinical staff often have little access to peer review. Objective. To describe the queries received from nurses by the hotline between 1 March and 31 May 2012 and identify problem areas and knowledge gaps where nurses may require further training. Methods. All queries received from nurses during the study period were analysed. An experienced information pharmacist reviewed all queries to identify knowledge gaps. Results. During the study period, the hotline received a total of 1 479 HIV- and TB-related queries from healthcare workers. Of these, 386 were received from nurses, of which 254 (66%) were NIMART-trained. The most common query subtopic was initiating antiretroviral therapy (ART) (20%), followed by adverse drug reactions (18%). The most common knowledge gap identified was the ability to interpret laboratory results before initiating ART (10%). Discussion. We conclude that the hotline is providing clinical help to an increasing number of nurses on the topic of treating HIV and TB throughout South Africa. In addition, queries directed to the hotline may assist in identifying knowledge gaps for the further training of nurses

Comparison of Mantoux and Tine Tuberculin Skin Tests in BCG-Vaccinated Children Investigated for Tuberculosis

BACKGROUND:Tuberculin skin tests (TSTs) are long-established screening methods for tuberculosis (TB). We aimed to compare agreement between the intradermal Mantoux and multipuncture percutaneous Tine methods and to quantify risk factors for a positive test result. METHODOLOGY/PRINCIPAL FINDINGS:1512 South African children younger than 5 years of age who were investigated for tuberculosis (TB) during a Bacille Calmette Guerin (BCG) trial were included in this analysis. Children underwent both Mantoux and Tine tests. A positive test was defined as Mantoux >or=15 mm or Tine >or= Grade 3 for the binary comparison. Agreement was evaluated using kappa (binary) and weighted kappa (hierarchical). Multivariate regression models identified independent risk factors for TST positivity. The Mantoux test was positive in 430 children (28.4%) and the Tine test in 496 children (32.8%, p<0.0001), with observed binary agreement 87.3% (kappa 0.70) and hierarchical agreement 85.0% (weighted kappa 0.66). Among 173 children culture-positive for Mycobacterium tuberculosis, Mantoux was positive in 49.1% and Tine in 54.9%, p<0.0001 (kappa 0.70). Evidence of digit preference was noted for Mantoux readings at 5 mm threshold intervals. After adjustment for confounders, a positive culture, suggestive chest radiograph, and proximity of TB contact were risk factors for a positive test using both TST methods. There were no independent associations between ethnicity, gender, age, or over-crowding, and TST result. CONCLUSIONS/SIGNIFICANCE:The Tine test demonstrated a higher positive test rate than the Mantoux, with substantial agreement between TST methods among young BCG-vaccinated children. TB disease and exposure factors, but not demographic variables, were independent risk factors for a positive result using either test method. These findings suggest that the Tine might be a useful screening tool for childhood TB in resource-limited countries

Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial comparing two dosing schedules

<p>Abstract</p> <p>Background</p> <p>Tuberculosis contributes significantly to morbidity and mortality among HIV-infected children in sub-Saharan Africa. Isoniazid prophylaxis can reduce tuberculosis incidence in this population. However, for the treatment to be effective, adherence to the medication must be optimized. We investigated adherence to isoniazid prophylaxis administered daily, compared to three times a week, and predictors of adherence amongst HIV-infected children.</p> <p>Methods</p> <p>We investigated adherence to study medication in a two centre, randomized trial comparing daily to three times a week dosing of isoniazid. The study was conducted at two tertiary paediatric care centres in Cape Town, South Africa. Over a 5 year period, we followed 324 HIV-infected children aged ≥ 8 weeks. Adherence information based on pill counts was available for 276 children. Percentage adherence was calculated by counting the number of pills returned. Adherence ≥ 90% was considered to be optimal. Analysis was done using summary and repeated measures, comparing adherence to the two dosing schedules. Mean percentage adherence (per child during follow-up time) was used to compare the mean of each group as well as the proportion of children achieving an adherence of ≥ 90% in each group. For repeated measures, percentage adherence (per child per visit) was dichotomized at 90%. A logistic regression model with generalized estimating equations, to account for within-individual correlation, was used to evaluate the impact of the dosing schedule. Adjustments were made for potential confounders and we assessed potential baseline and time-varying adherence determinants.</p> <p>Results</p> <p>The overall adherence to isoniazid was excellent, with a mean adherence of 94.7% (95% confidence interval [CI] 93.5-95.9); similar mean adherence was achieved by the group taking daily medication (93.8%; 95% CI 92.1-95.6) and by the three times a week group (95.5%; 95% CI 93.8-97.2). Two-hundred and seventeen (78.6%) children achieved a mean adherence of ≥ 90%. Adherence was similar for daily and three times a week dosing schedules in univariate (odds ratio [OR] 0.88; 95% CI 0.66-1.17; <it>P </it>= 0.38) and multivariate (adjusted OR 0.85; 95% CI 0.64-1.11; <it>P </it>= 0.23) models. Children from overcrowded homes were less adherent (adjusted OR 0.71; 95% CI 0.54-0.95; <it>P </it>= 0.02). Age at study visit was predictive of adherence, with better adherence achieved in children older than 4 years (adjusted OR 1.96; 95% CI 1.16-3.32; <it>P </it>= 0.01).</p> <p>Conclusion</p> <p>Adherence to isoniazid was excellent regardless of the dosing schedule used. Intermittent dosing of isoniazid prophylaxis can be considered as an alternative to daily dosing, without compromising adherence or efficacy.</p> <p>Trial registration</p> <p>Clinical Trials NCT00330304</p

Urine lipoarabinomannan testing for diagnosis of pulmonary tuberculosis in children: a prospective study

Background Urine tests for mycobacterial lipoarabinomannan might be useful for point-of-care diagnosis of tuberculosis in adults with advanced HIV infection, but have not been assessed in children. We assessed the accuracy of urine lipoarabinomannan testing for the diagnosis of pulmonary tuberculosis in HIV-positive and HIV-negative children. Methods We prospectively recruited children (aged ≤15 years) who presented with suspected tuberculosis at a primary health-care clinic and paediatric referral hospital in South Africa, between March 1, 2009, and April 30, 2012. We assessed the diagnostic accuracy of urine lipoarabinomannan testing with lateral fl ow assay and ELISA, with mycobacterial culture of two induced sputum samples as the reference standard. Positive cultures were identifi ed by acid-fast staining and tested to confi rm Mycobacterium tuberculosis and establish susceptibility to rifampicin and isoniazid. Findings 535 children (median age 42·5 months, IQR 19·1–66·3) had urine and two induced specimens available for testing. 89 (17%) had culture-confi rmed tuberculosis and 106 (20%) had HIV. The lateral fl ow lipoarabinomannan test showed poor accuracy against the reference standard, with sensitivity of 48·3% (95% CI 37·6–59·2), specifi city of 60·8% (56·1–65·3), and an area under the receiver operating characteristic curve of 0·53 (0·46–0·60) for children without HIV and 0·64 (0·51–0·76) for children with HIV. ELISA had poor sensitivity in children without HIV (sensitivity 3·0%, 95% CI 0·4–10·5) and children with HIV (0%, 0·0–14·3); overall specifi city was 95·7% (93·4–97·4). Interpretation Urine lipoarabinomannan tests have insuffi cient sensitivity and specifi city to diagnose HIV-positive and HIV-negative children with tuberculosis and should not be used in this patient population

Succession and determinants of the early life nasopharyngeal microbiota in a South African birth cohort

Background: Bacteria colonizing the nasopharynx play a key role as gatekeepers of respiratory health. Yet, dynamics of early life nasopharyngeal (NP) bacterial profiles remain understudied in low- and middle-income countries (LMICs), where children have a high prevalence of risk factors for lower respiratory tract infection. We investigated longitudinal changes in NP bacterial profiles, and associated exposures, among healthy infants from low-income households in South Africa. Methods: We used short fragment (V4 region) 16S rRNA gene amplicon sequencing to characterize NP bacterial profiles from 103 infants in a South African birth cohort, at monthly intervals from birth through the first 12 months of life and six monthly thereafter until 30 months. Results: Corynebacterium and Staphylococcus were dominant colonizers at 1 month of life; however, these were rapidly replaced by Moraxella- or Haemophilus-dominated profiles by 4 months. This succession was almost universal and largely independent of a broad range of exposures. Warm weather (summer), lower gestational age, maternal smoking, no day-care attendance, antibiotic exposure, or low height-for-age z score at 12 months were associated with higher alpha and beta diversity. Summer was also associated with higher relative abundances of Staphylococcus, Streptococcus, Neisseria, or anaerobic gram-negative bacteria, whilst spring and winter were associated with higher relative abundances of Haemophilus or Corynebacterium, respectively. Maternal smoking was associated with higher relative abundances of Porphyromonas. Antibiotic therapy (or isoniazid prophylaxis for tuberculosis) was associated with higher relative abundance of anerobic taxa (Porphyromonas, Fusobacterium, and Prevotella) and with lower relative abundances of health associated-taxa Corynebacterium and Dolosigranulum. HIV-exposure was associated with higher relative abundances of Klebsiella or Veillonella and lower relative abundances of an unclassified genus within the family Lachnospiraceae. Conclusions: In this intensively sampled cohort, there was rapid and predictable replacement of early profiles dominated by health-associated Corynebacterium and Dolosigranulum with those dominated by Moraxella and Haemophilus, independent of exposures. Season and antibiotic exposure were key determinants of NP bacterial profiles. Understudied but highly prevalent exposures prevalent in LMICs, including maternal smoking and HIV-exposure, were associated with NP bacterial profiles

Breath can discriminate tuberculosis from other lower respiratory illness in children

Pediatric tuberculosis (TB) remains a global health crisis. Despite progress, pediatric patients remain difficult to diagnose, with approximately half of all childhood TB patients lacking bacterial confirmation. In this pilot study (n = 31), we identify a 4-compound breathprint and subsequent machine learning model that accurately classifies children with confirmed TB (n = 10) from children with another lower respiratory tract infection (LRTI) (n = 10) with a sensitivity of 80% and specificity of 100% observed across cross validation folds. Importantly, we demonstrate that the breathprint identified an additional nine of eleven patients who had unconfirmed clinical TB and whose symptoms improved while treated for TB. While more work is necessary to validate the utility of using patient breath to diagnose pediatric TB, it shows promise as a triage instrument or paired as part of an aggregate diagnostic scheme

Safety and tolerability of single low-dose primaquine in a low-intensity transmission area in South Africa: an open-label, randomized controlled trial

Abstract Background To reduce onward falciparum malaria transmission, the World Health Organization recommends adding single low-dose (SLD) primaquine to artemisinin-based combination treatment in low transmission areas. However, uptake of this recommendation has been relatively slow given concerns about whether individual risks justify potential community benefit. This study was undertaken to generate comprehensive local data on the risk–benefit profile of SLD primaquine deployment in a pre-elimination area in South Africa. Methods This randomized, controlled open-label trial investigated adding a single low primaquine dose on day 3 to standard artemether–lumefantrine treatment for uncomplicated falciparum malaria. Efficacy, safety and tolerability of artemether–lumefantrine and primaquine treatment were assessed on days 3, 7, 14, 28 and 42. Lumefantrine concentrations were assayed from dried blood spot samples collected on day 7. Results Of 217 patients screened, 166 were enrolled with 140 randomized on day 3, 70 to each study arm (primaquine and no primaquine). No gametocytes were detected by either microscopy or PCR in any of the follow-up samples collected after randomization on day 3, precluding assessment of primaquine efficacy. Prevalence of the CYP2D6*4, CYP2D6*10 and CYP2D6*17 mutant alleles was low with allelic frequencies of 0.02, 0.11 and 0.16, respectively; none had the CYP2D6*4/*4 variant associated with null activity. Among 172 RDT-positive patients G6PD-genotyped, 24 (14%) carried the G6PD deficient (A−) variant. Median haemoglobin concentrations were similar between treatment arms throughout follow-up. A third of participants had a haemoglobin drop > 2 g/dL; this was not associated with primaquine treatment but may be associated with G6PD genotype [52.9% (9/17) with A− genotype vs. 31% (36/116) with other genotypes (p = 0.075)]. Day 7 lumefantrine concentrations and the number and nature of adverse events were similar between study arms; only one serious adverse event occurred (renal impairment in the no primaquine arm). The artemether–lumefantrine PCR-corrected adequate clinical and parasitological response rate was 100%, with only one re-infection found among the 128 patients who completed 42-day follow-up. Conclusions Safety, tolerability, CYP2D6 and G6PD variant data from this study support the deployment of the WHO-recommended SLD primaquine without G6PD testing to advance malaria elimination in South African districts with low-intensity residual transmission. Trial registration Pan African Clinical Trial Registry, PACTR201611001859416. Registered 11 November 2016, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=185

Cytomegalovirus acquisition in infancy and the risk of tuberculosis disease in childhood: a longitudinal birth cohort study in Cape Town, South Africa

BACKGROUND: The risk of tuberculosis disease after recent exposure is greatest before age 5 years; however, the mechanisms explaining this increased risk are not well elucidated. Acquisition of viral infections, such as cytomegalovirus, in early life might modulate the immune system. We aimed to evaluate the acquisition of cytomegalovirus infection in infancy and the development of tuberculosis disease in children. METHODS: In this prospective, birth cohort study we enrolled pregnant women who were between 20 and 28 weeks of gestation attending antenatal care in Paarl, a periurban setting outside of Cape Town, South Africa. Participants were recruited from two clinics (TC Newman and Mbekweni). Infants were given Bacillus Calmette-Guérin vaccination at birth as per national policy. Nasopharyngeal swabs for cytomegalovirus detection using qPCR were done for infants at birth, age 3 and 6 weeks, and age 3, 6, 12, and 24 months. Children were prospectively followed up for tuberculosis disease until age 9 years using tuberculin skin testing, radiographic examinations, GeneXpert, and sputum testing. Tuberculin skin tests were done at the 6-month visit and then at age 12, 24, 36, 48, and 60 months, and at the time of lower respiratory tract infection. We compared tuberculosis disease incidence after age 1 year or after age 6 months in children with and without cytomegalovirus infection using Cox regression and hazard ratios (HRs) with 95% CIs. FINDINGS: Between March 5, 2012, and March 31, 2015, 1225 pregnant women were recruited and enrolled in the birth cohort. 88 (7%) women were excluded because of loss to antenatal follow-up or pregnancy losses. Of 1143 livebirths, 68 (6%) mother-infant pairs were excluded. In total, 963 children were serially tested for cytomegalovirus (7186 cytomegalovirus measurements taken; median six tests per child, IQR 2-11). The prevalence of congenital cytomegalovirus at age younger than 3 weeks was 2% (18 of 816). Cytomegalovirus positivity increased continuously with age from 3% (27 of 825) by age 6 weeks to 21% (183 of 882) by 3 months, 35% (315 of 909) by 6 months, and 42% (390 of 933) by 12 months. Mother-infant pairs were followed up for a median of 6·9 years (IQR 6·0-7·8). The risk of tuberculosis disease in children after age 1 year was higher in those with cytomegalovirus infection by age 6 weeks (adjusted HR 4·1, 95% CI 1·2-13·8; p=0·022), 3 months (2·8, 1·4-5·8; p=0·0040), 6 months (3·6, 1·7-7·3; p<0·0001), 12 months (3·2, 1·6-6·4; p=0·0010), and 24 months (4·2, 2·0-8·8; p<0·0001). The risk of microbiologically confirmed tuberculosis disease was also higher among children acquiring cytomegalovirus infection before age 3 months (adjusted HR 3·2, 95% CI 1·0-10·6; p=0·048), 6 months (3·9, 1·2-13·0; p=0·027), 12 months (4·4, 1·2-16·3; p=0·027), and 24 months (6·1, 1·3-27·9; p=0·020). In children older than 1 year, the risk of tuberculosis disease was consistently greater in those with high cytomegalovirus loads than in those with low cytomegalovirus loads that were acquired before age 3 months (adjusted HR 2·0 vs 3·7; ptrend=0·0020; both groups compared with cytomegalovirus negative reference) and before age 12 months (2·7 vs 3·7; ptrend=0·0009). INTERPRETATION: Infants that acquire cytomegalovirus in the first year of life are at high risk of subsequently developing tuberculosis disease. Efforts to prevent tuberculosis in early childhood in high-burden countries might need to deter or delay acquisition of cytomegalovirus perinatally or in the first months of life. FUNDING: Bill & Melinda Gates Foundation, MRC South Africa, National Research Foundation South Africa, and Wellcome Trust